Immuno-antibiotics: targeting microbial metabolic pathways sensed by unconventional T cells.

Matthias Eberl,Eric Oldfield,Thomas Herrmann

doi:10.1093/immadv/ltab005

Abstract

SummaryHuman Vγ9/Vδ2 T cells, mucosal-associated invariant T (MAIT) cells, and other unconventional T cells are specialised in detecting microbial metabolic pathway intermediates that are absent in humans. The recognition by such semi-invariant innate-like T cells of compounds like (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMB-PP), the penultimate metabolite in the MEP isoprenoid biosynthesis pathway, and intermediates of the riboflavin biosynthesis pathway and their metabolites allows the immune system to rapidly sense pathogen-associated molecular patterns that are shared by a wide range of micro-organisms. Given the essential nature of these metabolic pathways for microbial viability, they have emerged as promising targets for the development of novel antibiotics. Here, we review recent findings that link enzymatic inhibition of microbial metabolism with alterations in the levels of unconventional T cell ligands produced by treated micro-organisms that have given rise to the concept of ‘immuno-antibiotics’: combining direct antimicrobial activity with an immunotherapeutic effect via modulation of unconventional T cell responses.

Highlights

Unconventional T cells represent a class of T cells that — unlike conventional CD4+ and CD8+ T cells — play a crucial role in sensing danger in the absence of classical restriction via the major histocompatibility complex (MHC)
There are two well-characterised populations of unconventional T cells which stand out with regard to their relative abundance in the human body, their broad reactivity toward microbial metabolites shared by a wide range of pathogens, and their ease of manipulation in vitro: Vγ9/Vδ2 T cells and mucosal-associated invariant T (MAIT) cells [2]
We review progress and prospects for targeting microbial metabolic pathways for both direct as well as indirect, unconventional T cell-based killing of pathogens, as well as immunomodulation in general

Summary

Introduction

Unconventional T cells represent a class of T cells that — unlike conventional CD4+ and CD8+ T cells — play a crucial role in sensing danger in the absence of classical restriction via the major histocompatibility complex (MHC). Targeted deletion of genes encoding enzymes upstream of the generation of HMB-PP leads to a drastically reduced capacity of bacterial mutants to activate Vγ9/Vδ2 T cells *24,25,26,28].

Results

Conclusion